The Epidemiology Branch is conducting a number of birth defect studies in collaboration with the Health Research Board and Trinity College, Dublin, Ireland. The main objective of these studies is to determine the relationship between folate and birth defects. The birth defects studied to date are neural tube defects (NTDs), oral clefts, congenital heart defects,Down syndrome and omphalocele. These studies focus on biochemical factors in the area of folate metabolism, and on genetic mutations in folate related genes associated with birth defects. In the past we have shown that elevated homocysteine is a risk factor for NTDs, that a mutation in the methylenetetrahydrofolate reductase (MTHFR) gene 677C->T is a risk factor for NTDs, and that a small dose of folic acid (100-200 micrograms) can raise red cell folate to levels that can prevent a fifth to almost a half of NTDs. We have shown that methylenetetrahydrofolate reductase (MTHFD), an important gene in the production of purine and pyrimidine for DNA synthesis in a risk factor for NTDs. Mothers who have the R653Q variant of this gene are at increased risk of having a child with an NTD. This is the first maternal gene to be shown to be a risk factor for NTDs. Recently, we published a report showing that MTHFR C677T is not only a risk factor in the homozygous, but in the heterozygous state as well. This is important because over 50% of the population has a least one copy of the C677T variant. We have completed data and sample collection for genetic analysis on subjects with oral clefts and their families and samples from children with congenital heart defects and normal controls. We have samples from over 900 subjects with cleft lip or palate and from over 2000 children with congenital heart defects. These subjects will be studied to determine whether folate-related genes are etiologically important in clefts and congenital heart defects. We have also collected and analyzed DNA from 25 children with omphalocele who do not have chromosomal defects and are investigating possible relationships with candidate genes.